The inflammatory bowel diseases (IBD) are comprised of Crohn's disease and ulcerative colitis and affect approximately 1.4 million Americans. Present medical therapies are incompletely effective. Enormous progress in defining genes contributing to IBD has been made possible through large Consortial efforts which leverage large sample sizes and complementary expertise. We present new data from the Immunochip, a collaborative international effort involving the analysis of over 75,000 samples that has resulted in the identification of 163 loci associated with IBD. A major goal of the field, moving forward, is to derive a more cohesive picture of IBD pathogenesis which moves from identifying myriad genetic loci to an approach which draws out whole pathways to deepen our understanding of the biology of the disease. In Specific Aim 1, we propose to actively participate as a genetics research center (GRC) within the larger NIDDK IBD Genetics Consortium. Future progress will be enhanced by drawing in investigators with complementary expertise. In addition to present genetic, clinical and statistical expertise in the Yale GRC, we have added expertise in mucosal immunology and host-mycobacterial interactions. We will continue to provide sample material attached to relevant information useful for genetic and genomic studies. In Specific Aim 2, we propose to define the underlying genetic architecture of IBD that has been shaped by host-microbe interactions. We identify evidence for natural selection driving many of association signals, likely driven by host-microbial interactions. We have identified a new IBD association to a region on chromosome 19q13 containing the LILR-KIR gene families. This region has been profoundly shaped by balancing selection, and a complete genetic definition of this region has been hampered by phasing challenges. We propose an innovative approach to define genetic variation in this region through long-range sequence reads in diverse populations that will resolve present phasing challenges. A striking overlap of IBD loci with mycobacterial susceptibility loci is observed, and a NOD2- focused analysis of a macrophage-enriched inflammatory module identifies additional IBD-associated genes nearby in the network that modulate host responses to mycobacterial infection. In order to provide a more cohesive understanding of the functional genomic responses, we propose studies to compare the expression and functional responses of human macrophages in response to mycobacterial infection between IBD patients and controls, and across populations. Combined with integrated, tissue-based Bayesian network analyses, these studies will deepen our understanding of the underlying mechanisms of IBD. This understanding is critical for the development of novel therapies to improve our treatment of patients affected by these often debilitating disorders.